Efficacy of Ketoprofen With or Without Omeprazole for Pain And Inflammation Control After Third Molar Removal - SciELO

Brazilian Dental Journal (2018) 29(2): 140-149
                                                                                                    ISSN 0103-6440

Efficacy of Ketoprofen With or Without
                                                                                                    1Department  of Biological
                                                                                                    Sciences, Bauru School of
                                                                                                    Dentistry, USP - Universidade de
Omeprazole for Pain And Inflammation                                                                São Paulo, Bauru, SP, Brazil
                                                                                                    2Department of Pediatric Dentistry,

Control After Third Molar Removal                                                                   Orthodontics and Community
                                                                                                    Health, Bauru School of Dentistry,
                                                                                                    USP - Universidade de São
                                                                                                    Paulo, Bauru, SP, Brazil

Luis Fernando Simoneti1, Giovana Maria Weckwerth1, Thiago José Dionísio1,
Elza Araujo Torres1, Paulo Zupelari-Gonçalves1, Adriana Maria Calvo1, José                          Correspondence: Carlos F. Santos,
Roberto Lauris2, Flávio Cardoso Faria1, Carlos Ferreira Santos1                                     Alameda Octávio Pinheiro Brisolla,
                                                                                                    975, 17012-901. Bauru, SP, Brazil.
                                                                                                    Phone/Fax: +55 14 32358295.
                                                                                                    e-mail: cfsantos@fob.usp.br

In view of the gastrointestinal problems generated by the ketoprofen use, the ketoprofen
association with omeprazole is available on the market. However, this association efficacy
in acute pain control has not been established. Bilateral extraction of lower third molars
in similar positions is currently the most used model for the evaluation and investigation
of the efficacy and pharmacological effects of new compounds for the treatment of acute
postoperative pain. The randomized and crossover study consisted in evaluating the clinical
efficacy of therapy performed by ketoprofen 100 mg (twice daily–b.i.d.) versus ketoprofen
200 mg + omeprazole 20 mg (once daily-q.d.) to pain, swelling and trismus control in
the bilateral extraction model of lower third molars in similar positions in two different
appointments, in 50 volunteers. Volunteers reported significantly less postoperative
pain at various post-operative periods and consumed less rescue analgesic medication
(acetaminophen 750 mg) throughout the study when they took the combination of
ketoprofen 200 mg + omeprazole 20 mg (q.d.). Following administration of both study
drugs, no gastrointestinal adverse reactions were reported by volunteers. Furthermore,
the evaluations of the drugs in pain control by the volunteers were significantly favorable
to ketoprofen 200 mg + omeprazole 20 mg (q.d.). For swelling and trismus control, the
treatments presented similar results. In conclusion, when volunteers took ketoprofen
200 mg + omeprazole 20 mg (q.d.), they reported significantly less postoperative pain at            Keywords: ketoprofen,
various post-surgical periods and consumed less rescue analgesic medication throughout              omeprazole, pain control,
the study compared with ketoprofen 100 mg (b.i.d).                                                  lower third molar surgery.

Introduction                                                              of limitation of mouth opening is expected.
     Bilateral extraction of lower third molars in similar                    To prevent the occurrence of postoperative
positions is currently the most used model for the evaluation             complications, such as acute pain, studies indicate the
and investigation of the efficacy and pharmacological                     use of physical procedures, such as the use of cold packs
effects of new compounds for the treatment of postoperative               soon after the surgeries. In addition to these procedures,
pain, such as analgesics and anti-inflammatory drugs (1,2).               non-steroidal anti-inflammatory drugs (NSAIDs) have been
This type of surgical procedure is recommended since some                 extensively used as adjuvants for the reduction of these
tissues are manipulated and traumatized in the region                     postoperative complications derived from the extractions
where the extraction is performed, composed mainly of                     of the lower third molars (1,2,8,9).
loose connective tissue that contains blood and lymphatic                     Scientific evidence demonstrates that NSAIDs exhibit
vessels. Due to their manipulation, a number of functional                their therapeutic effect by inhibiting cyclooxygenase
and structural changes are expected; among them are the                   (COX), and this inhibits the production of prostaglandins
release of exudate and the formation of swelling, with                    (PGs) and thromboxanes. According to the literature, PGs
subsequent onset of trismus and pain (3-5).                               alone do not cause pain, but they potentiate the action of
     Pain resulting from the extraction of third molars is                chemical mediators of inflammation, such as bradykinin
usually short in duration and of moderate intensity, with                 on the nociceptive fibers, which consequently cause pain
greater pain intensity soon after the surgical procedure                  amplification (10). COX is known in two isoforms: COX-1,
(6). Swelling is formed due to tissue manipulation during                 and COX-2. A third isoform of this enzyme family, known as
surgery, and presents maximum intensity after 48 h of the                 COX-3 has been discovered, which unlike COX-1 and COX-
surgical procedure (7). Trismus after third molar extraction              2, would not produce proinflammatory prostanoids, but
is closely related to the level of swelling and inflammation              rather anti-inflammatory substances. COX-1 is known as a
generated by the surgery, ie, the greater the level of swelling           constitutive enzyme. It is associated with the production of
resulting from an inflammatory response, the greater degree               prostaglandins and results in several physiological effects,
Braz Dent J 29(2) 2018

such as gastric protection, platelet aggregation, vascular        mg tablets (b.i.d.) versus ketoprofen 200 mg + omeprazole
homeostasis and maintenance of renal blood flow (11).             20 mg (q.d.), both administered enterally for the control
    NSAIDs are commonly prescribed to combat a                    of pain, swelling and trismus in the bilateral extraction
wide variety of inflammatory pain conditions such as              model of lower third molars with similar positions in two
osteoarthritis, rheumatic diseases, soft tissue trauma, and       different appointments.
postoperative pain. NSAIDs are also commonly used in
dental practice, such as in the treatment of orofacial pain       Material and Methods
or pain after surgical procedures such as dental extractions          The present randomized and cross-over study was
(1,2,8,9). Ketoprofen is a non-steroidal anti-inflammatory        performed in volunteers regularly enrolled at the Bauru
drug, derived from arylcarboxylic acid, belonging to the          School of Dentistry, University of São Paulo, after
propionic acid group of NSAIDs. Ketoprofen has anti-              approval by the Institutional Review Board (CAAE:
inflammatory, antipyretic and peripheral and central              44808215.6.0000.5417) in accordance with the Declaration
analgesic activity. It inhibits the synthesis of prostaglandins   of Helsinki for Human Research. The clinical trial was
and platelet aggregation, however, its mechanism of action        registered under ID # NCT02730026 at ClinicalTrials.gov.
is not completely elucidated (10,12). Evidence from a             The present study included healthy individuals (ASA I
number of clinical studies suggests that ketoprofen is an         according to the classification of the American Society of
effective analgesic, with its therapeutic effect generally at     Anesthesiologists) of both sexes, aged 18-38 years, with
doses ranging from 75 to 300 mg per day (12). Omeprazole is       indication of bilateral third molar extraction.
a potent inhibitor of H+/K+ ATPase (proton pump inhibitor),           Volunteers could not have inflammations or infections
which is responsible for the secretion of hydrochloric acid       prior to surgical procedures, such as pericoronitis, alveolitis,

                                                                                                                                     Ketoprofen with or without omeprazole for pain
by parietal gastric cells. Omeprazole was well established        osteonecrosis or mucositis. In addition, the volunteers
as a highly effective inhibitor of acid secretion. The drug       signed the Informed Consent Form. In order to standardize
has a long duration of action. Remaining acid secretion           the sample, the volunteers should present the positions of
is significantly reduced at 21 days after withdrawal of           the lower third molars, roots and similar degree of impaction
omeprazole 20 mg/day for 4 weeks in volunteers with               on the right and left sides of the mouth according to the
duodenal ulcer. The effect of omeprazole on gastric acid          classification of Pell and Gregory as well as Winter (16),
secretion is dose-dependent (13,14).                              which was confirmed by orthopantomographic radiography
    In the international literature, several NSAIDs have been     and clinical examination.
studied in randomized, cross-over models, demonstrating               Eligibility criteria included adults without inflammation,
their efficacy in the management of acute pain after              infection and systemic diseases that could possibly interfere
bilateral extraction of lower third molars in similar positions   with the study. Exclusion criteria were as follows: any history
(1,2,8,9). This study model of bilateral removal of lower         of allergy, gastrointestinal bleeding/ulcers, kidney disease,
third molars with similar positions is unique, since the          asthma or any known allergic sensitivity to ketoprofen,
same surgery is essentially performed twice in the same           omeprazole or any NSAID. Pregnant or lactating women
patient, and will serve as its own control, thus avoiding         were also excluded from the study, as well as volunteers
response variations (10).                                         who used antidepressants, diuretics or NSAIDs 7 days prior
    In view of the gastrointestinal problems generated            to the start of the experiments (1,2,8,9).
by the use of ketoprofen, the association of ketoprofen               All lower third molars extractions were performed
with omeprazole is available on the market. However, the          with the same technique and with the same magnitude
efficacy of this association in the acute control of pain has     of surgical trauma, all third molars were impacted, with
not been established. In the combination of ketoprofen            necessity of bone removal on both opposing sides of the
200 mg + omeprazole 20 mg the pharmacokinetic                     mandible in each of the volunteers of the research. All
profiles of the ketoprofen and omeprazole components              surgeries were performed by the same oral & maxillofacial
are comparable to those of the separately administered            surgeon (L.F.S.) and assisted by the same assistant in two
ketoprofen and omeprazole components, but the                     different appoints, being performed in two visits with
formulation has a sustained release form of ketoprofen            intervals of one to two months. The choice of the side to be
and a gastroresistant release form of omeprazole, both            operated on and the NSAID to be used [ketoprofen 100 mg
suitable for once-daily therapeutic dosing. There is no           twice daily (b.i.d.) (Profenid®, Sanofi-Aventis Farmacêutica
influence on the pharmacokinetics of ketoprofen when              Ltda, Suzano/SP, Brazil) or ketoprofen 200 mg + omeprazole
administered concomitantly with omeprazole, and vice              20 mg once daily (q.d.) (Profenid Protect®, Sanofi-Aventis
versa (15). Therefore, the objective of the present study         Farmacêutica Ltda, Suzano/SP, Brazil), each hard gelatin
was to evaluate the clinical efficacy of ketoprofen 100           capsule contains 200 mg of ketoprofen (extended-release
Braz Dent J 29(2) 2018

                         microgranules) and 20 mg of omeprazole (gastroresistant             •    Subjective evaluation of postoperative pain, which
                         microgranules) for 4 days] was done in a randomized                      was recorded by the volunteer himself on a Visual
                         manner using a randomization worksheet obtained through                  Analog Scale (0 to 100 mm). Subjective pain
                         the program available at: http://www.randomization.com,                  assessments were performed by volunteers at the
                         number 19482.                                                            following times after administration of the drugs
                             The randomization determined which side would be                     [0; 15; 30 and 45 min, 1; 1.5; 2; 3; 4; 5; 6; 7; 8;
                         operated and the drug to be prescribed in the first surgery.             10; 12; 16; 24, 48, 72 and 96 h];
                         Therefore, in the second surgery the opposite side would            •    Mouth opening (distance in mm between the
                         be operated and the other drug prescribed. The drugs                     edges of the upper and lower incisors during the
                         were coded in even and odd numbers and the only person                   maximum opening achieved by the volunteer)
                         responsible for prescribing the postoperative medication                 before the surgery, on the 2nd postoperative
                         knew which drug was being prescribed. This information                   day and at the time of sutures removal (7th day,
                         was not disclosed to researchers until the end of the study.             respectively). The postoperative ability to open
                             All anesthetic procedures were performed with blockade               the mouth was expressed as a percentage of the
                         of the buccal, lingual and inferior alveolar nerves, initially           preoperative measurement;
                         administering a cartridge (1.8 mL) of local anesthetic.             •    Onset and duration of surgery after anesthetic
                         After anesthesia of the lower lip, half a cartridge (0.9 mL)             administration;
                         of another tube not yet used and of the same anesthetic             •    Patients were asked if they experienced any
                         solution was administered by an infiltrative terminal                    discomfort and/or side effects at the time of
                         technique to diminish hemorrhage and guarantee mucosal                   appointment for suture removal;
                         anesthesia. The local anesthetic used was 4% articaine              •    Total amount of pain relief medication used
                         with 1:200,000 epinephrine, according to our laboratory                  (acetaminophen 750 mg);
                         studies (2,8,9,17,18).                                              •    Measurement of facial swelling on the 2nd
L. F. Simoneti et. al.

                             As a rescue analgesic medication, if the volunteer judged            postoperative day and on the 7th postoperative
                         that the analgesia produced by the anti-inflammatory                     day (removal of stitches) and quality of healing.
                         drug provided was insufficient, acetaminophen (EMS S/A,
                         Hortolândia/SP, Brazil) was prescribed at 750 mg every 8 h       Statistical Analysis
                         (2,8,9,17-20). Throughout the surgical procedure, notations          G*Power software v.3.0.10 was used for the sample
                         were made such as: the amount of anesthetic administered,        calculation. Data were tabulated using Microsoft® Excel
                         the hemodynamic data of the volunteer at each surgical           2012 (version 10.6871.6870) and GraphPad Prism (version
                         stage through the DX 2021 Dixtal device (Biomédica Ind e         4.0) was used to perform statistical analysis. For comparison
                         Com Ltda, Marília/SP, Brazil), the amount of bleeding and        of some parameters proposed in the study the paired t test
                         the degree of difficulty of each stage of surgery (incision,     for the parametric data and the Wilcoxon test for non-
                         flap, osteotomy, tooth section, extraction, cleaning and         parametric data were used. For the analysis of pain data,
                         suturing) (1,2,8,9,17-19,21).                                    Friedman test was used because the data are not parametric.
                             As soon as the procedure was finished, the volunteer         For the mouth opening and trismus analyzes the two-way
                         immediately received the first anti-inflammatory tablet          ANOVA was used since the data are parametric. Mean ±
                         according to the randomization (ketoprofen 100 mg b.i.d. or      standard deviations were used to express the parametric
                         ketoprofen 200 mg + omeprazole 20 mg q.d.) and received          data. Median [interquartile ranges] were used to express
                         a pain chart, in which he noted the exact times he took          the non-parametric data. The level of significance adopted
                         his medication, according to the time of the end of the          was 5%.
                         surgery. In this pain chart, the volunteer was instructed            The sample size calculation was performed based on
                         to report any gastrointestinal adverse reaction, fill out if     mouth opening, trismus, amount of rescue medication and
                         there was a need for ingestion of the rescue medication          pain 8h after the surgery (peak) data from previously studies
                         (acetaminophen 750 mg), and the volunteer was instructed         (8,9). The minimal effect size was 0.37741, the power was
                         to complete a Visual Analog Scale (0 to 100 mm) for              70% and the significance level was 5%.
                         postoperative pain, which contained «no pain (0 mm)»
                         and «worst pain possible (100 mm)». No antibiotics were          Results
                         prescribed to the volunteers due to the pharmacological              After the eligibility evaluation, the study consisted of 54
                         protocol applied in the present research, which corroborates     volunteers; of these, two volunteers evolved with purulent
                         previous studies by out group (22).                              discharge in the postoperative period, one patient became
                             The parameters evaluated were as follows (Table 1):          pregnant in the research development and one patient
Braz Dent J 29(2) 2018

had different duration of both surgeries, therefore these               ketoprofen 100 mg b.i.d. was 19.3 ± 5.8 min, and ketoprofen
4 volunteers they were excluded from the study with the                 200 mg + omeprazole 20 mg q.d. was 21 ± 7.7, without
total sample composed of 50 volunteers. There were 33                   a statistically significant difference (p = 0.0768, Table 3).
women (66%) and 17 men (34%) aged 18-38 years (mean                     In the postoperative pain scores documented by each
age 24 ± 5 years) (CONSORT flow chart, Fig. 1).                         volunteer there was a statistically significant difference
    Each of the 50 volunteers completing this study had                 in the periods of 1.5, 7, 8, 10, 12, 16, 24, 48 and 72 h
each of the lower third molars classified as IA (n = 24), IB            postoperative ketoprofen 100 mg b.i.d. and ketoprofen 200
(n = 3), IIA (n = 12), IIB (n = 9) and IIC (n = 2) according            mg + omeprazole 20 mg q.d. (p0.05) (Table 4).
q.d., osteotomies and tooth sectioning were performed                       When analyzed for swelling and trismus values, there
in 30 surgeries, only osteotomies in 12 surgeries, and 9                was no statistically significant difference in the sum of
did not require osteotomies and tooth sectioning. For all               the mean linear distances between the two drugs studied

                                                                                                                                                Ketoprofen with or without omeprazole for pain
these results, no significant statistical difference was found          (p>0.05). The swelling had its maximum peak significantly
regarding surgical trauma (Table 2).                                    increased during the second day, and did not return to
    The mean duration of surgery when volunteers received               baseline after the seventh day for both treatments (p
Braz Dent J 29(2) 2018

                         Regarding the maximum mouth opening, there was a                             present significant difference between the when volunteers
                         statistically significant difference (p0.05). Another parameter evaluated and that did not                       volunteers. In addition, no adverse reaction to the use of any
L. F. Simoneti et. al.

                         Figure 1: Study flowchart.

                         Figure 2. Visual analog scale (VAS) of self-reported postoperative pain      Figure 3. Self-reported global efficacy of oral ketoprofen 100 mg
                         scores after lower third molar surgeries assessed at 15, 30, 45 min and      b.i.d. and ketoprofen 200 mg + omeprazole 20 mg q.d. during
                         1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 48, 72 and 96 h. Scores could   the seventh postoperative day as assessed using a 5-level Likert
                         range from 0 to 100 mm with larger scores indicating increased pain.         scale (n = 50). The format of the Likert ratings was “excellent,”
                         Data are presented as median and interquartile range (n = 50). * Indicates   “very good,” “good,” “fair,” or “poor”. * Indicates a p-value
                         a p-value ≤ 0.05, Wilcoxon test, for each assessed time period comparing     ≤ 0.05, Wilcoxon test for the “excellent” sub-group between
                         ketoprofen 100 mg b.i.d. and ketoprofen 200 mg + omeprazole 20 mg q.d.       research medications.
Braz Dent J 29(2) 2018

anesthetic solution was observed by the surgeon or reported                     pain, swelling and trismus control, significantly better
by the volunteers during and after the surgeries. There                         evaluated when compared to ketoprofen 100 mg b.i.d. (p
was also no statistically significant difference regarding                      = 0.0001) (Fig. 3).
the time of action of the local anesthetic 4%articaine
with 1:200,000 epinephrine, number of cartridges used                           Discussion
in each extraction and quality of anesthesia. In addition,                          The present randomized and cross-over study
during all surgeries, no hypertensive peaks were observed                       investigated the clinical efficacy of postoperative pain
in the systolic, diastolic and mean arterial pressure data.                     control, swelling, and trismus using enterally ketoprofen 100
The oxygen saturation, heart rate and bleeding index did                        mg once every 12 h and ketoprofen 200 mg in combination
not change significantly during the surgeries (Table 3).                        with omeprazole 20 mg administered once every 24 h, after
    There were statistically significant differences observed                   extractions of lower third molars under local anesthesia.
between the global evaluations of volunteers for ketoprofen                     As a method of evaluating acute postoperative pain, some
100 mg b.i.d. and ketoprofen 200 mg + omeprazole 20 mg                          researchers use analog visual scales, in which volunteers
q.d. According to the global postoperative evaluations of                       report the evaluation of the intensity of their pain
the volunteers, ketoprofen 200 mg + omeprazole 20 mg q.d.                       (1,2,8,9,23), as the present study, which used the visual
was classified as excellent and very good for postoperative                     analog scale to determine the intensity of postoperative

Table 2. Third molars position according to Pell & Gregory and Winter, number of surgeries without osteotomy and tooth sectioning, number of
surgeries with only osteotomy and number of surgeries with osteotomy and tooth sectioning.

                                                                                                                                                      Ketoprofen with or without omeprazole for pain
                                                               Ketoprofen 100 mg b.i.d.            Ketoprofen 200 mg + Omeprazole 20 mg q.d.
 IA                                                                        24

 IB                                                                        3

 IC                                                                        0

 IIA                                                                       12

 IIB                                                                       9

 IIC                                                                       2

 IIIA                                                                      0

 IIIB                                                                      0

 IIIC                                                                      0

 Vertical                                                                  27

 Horizontal                                                                17

 Distoangular                                                              6

 Mesioangular                                                              0

 Inverted                                                                  0

 Buccal/Lingual Obliquity                                                  0

 Surgeries without osteotomy and tooth sectioning                          9                                             9

 Surgeries with only osteotomy                                             9                                             11

 Surgeries with osteotomy and tooth sectioning                             32                                           30

Pell and Gregory classification based on the amount of tooth covered by the anterior border of the ramus: Class I 3rd molar impaction: Situated
anterior to the anterior border of the ramus, Class II 3rd molar impaction: Crown ½ covered by the anterior border of the ramus. Class III 3rd
molar impaction: Crown fully covered by the anterior border of the ramus. The depth of the impaction relative to the adjacent tooth (A,B,or C).
Class A: the occlusal plane of the impacted tooth is at the same level as the adjacent tooth. Class B: the occlusal plane of the impacted tooth is
between the occlusal plane and the cervical line of the adjacent tooth. Class C: the occlusal plane of the impacted tooth is apical to the cervical
line of the adjacent tooth. Winter classification: Mesio-Angular: The impacted tooth is tilted toward the 2nd molar in a mesial direction. Disto-
Angular: The long axis of the 3rd molar is angled distally / posteriorly away from the 2nd molar. Horizontal: The long axis of the 3rd molar is
horizontal. Vertical: The long axis of the 3rd molar is parallel to the long axis of the 2nd molar. Buccal / Lingual Obliquity: In combination with
the above, the tooth can be buccally (tilted towards the cheek) or lingually (tilted towards the tongue) impacted. Inverted: In this position, the
tooth is displaced in an upside down position, with the crown facing the alveolar nerve.
Braz Dent J 29(2) 2018

                         pain, ketoprofen 200 mg + omeprazole 20 mg q.d. had a                       in the present study, the results showed that ketoprofen
                         superior analgesic effect when compared to ketoprofen 100                   100 mg presented the highest pain intensity in the 10-hour
                         mg b.i.d., with a statistically significant difference in the               postoperative period. However, it is worth noting that for
                         control of pain, mainly in the periods of 1.5, 7, 8, 10, 12, 16,            both drugs evaluated, pain control was satisfactory since
                         24, 48 and 72 h postoperative. It is worth emphasizing at                   the volunteers reported less than 20 mm in the visual
                         this moment that the acute pain control after the surgeries                 analog scale score, which reflects in mild pain according
                         by both drugs was effective, since the literature reports                   to Hawker et al. 2011 (23).
                         that pain below 45 mm does not affect the daily routine                          Pain, swelling and trismus arising from the extraction of
                         of the volunteers (17,21,24).                                               lower third molars are usually influenced by some variables
                             The efficacy of ketoprofen 100 mg has also been                         such as time of surgery, medication, postoperative care
                         compared with methylprednisolone in pain control after                      and tissue manipulation (7). Data from the present study
                         third molar surgery, with peak pain intensity occurring                     revealed that the duration of surgery was the same when
                         within the first 12 h with the use of both drugs (12).                      volunteers were medicated either with ketoprofen 200
                         Although there were significant differences in pain scores                  mg + omeprazole 20 mg q.d. or ketoprofen 100 mg b.i.d.,
                                                                                                                                 thus demonstrating the reliability
                                                                                                                                 of the experimental model used
                         Table 3. Self-reported consumption of pain relief medication and pain scores when pain relief           in the present study since the
                         medication was consumed                                                                                 volunteers were submitted to
                                                          Amount of relief      Pain score    Time duration, surgery to          the same magnitude of surgical
                                                        medication (tablets)    (0 to 100)     1st relief medication (h)         trauma.
                          Ketoprofen 100 mg b.i.d.             3 [4.5]         29.7 ± 20.6              7.0 [5.7]                    Swelling derived from third
                          Ketoprofen 200 mg +                                                                                    molar    extractions presents
                                                              0.5 [3] *        27.7 ± 20.2              5.1 [5.4]
                          Omeprazole 20 mg q.d.                                                                                  maximum intensity after 48 h
L. F. Simoneti et. al.

                         Numbers reported with ± indicate a mean ± 1 SD, numbers reported with [ ] indicate a median and         of the surgical procedure (7).
                         IRQ* Indicates a p-value ≤ 0.05, Wilcoxon test versus ketoprofen 100 mg b.i.d.                          In the present study, swelling
                                                                                                                                 had its peak during the second
                                                                                                                                 postoperative day as reported
                         Table 4. Demographic distribution and intraoperative parameters of 50 volunteers undergoing            by the aforementioned study.
                         invasive lower third molar surgeries
                                                                                                                                After adding the linear measures
                                                                               Ketoprofen       Ketoprofren 200 mg +            of swelling and trismus of 48
                                                                              100 mg b.i.d      Omeprazole 20 mg q.d.
                                                                                                                                h and 7 days postoperatively
                          Age (years)                                           24 ± 5.0
                                                                                                                                and comparing with the
                          Male                                                  17 (34%)
                                                                                                                                baseline measurement, the data
                          Female                                                33 (66%)
                                                                                                                                demonstrated that there was no
                          Anesthetic (cartridges)                                1.5 [0]                  1.5 [0]               statistically significant difference
                          Surgery duration (min)                               19.3 ± 5.8               21.0 ± 7.7              between the medications,
                          Onset of local anesthetic (sec)                       116 ± 48                 113 ± 47               which shows that there was a
                          Anesthesia quality (1 to 3)                             1 [0]                    1 [0]                standardization of surgical trauma
                          Surgery difficulty (1 to 3)                             3 [1]                    3 [1]                in both, and that both ketoprofen
                          Intraoperative bleeding (1 to 3)                        1 [0]                    1 [0]                100 mg b.i.d. and ketoprofen 200
                          Wound-healing evaluation (1 to 3)                       1 [0]                    1 [0]                mg + omeprazole 20 mg q.d.
                          Preoperative period Mouth opening (mm)               47.3 ± 7.7               46.2 ± 6.7              were equalized in the control of
                          Mouth opening (mm) Second day                        29.9 ± 8.3#              28.1 ± 7.1#             postoperative swelling and trismus.
                          Mouth opening (mm) Seventh day                       38.4 ± 8.8#              37.1 ± 9.4#                 Another variable widely used to
                          Facial measurement (mm) Preoperative period         378.5± 24.0              377.7± 21.4              predict the difficulty of extracting
                          Facial swelling (mm) Second day                    398.1 ± 23.2#            394.6 ± 21.9#             the lower third molars, and
                          Facial swelling (mm) Seventh day                   386.1 ± 23.8#            383.8 ± 22.4#             influences the level of surgical
                          Body temperature (oC) Preoperative period           36.02 ± 0.77            36.06 ± 0.17              trauma, is the Pell and Gregory (9)
                          Body temperature (oC) Second day                    36.09 ± 0.55             36.36 ± 1.10             classification based on their spatial
                          Body temperature ( C) Seventh day
                                              o                               35.57 ± 0.50               36.00 ± 0              relationships with the ascending
                         Numbers reported with ± indicate a mean ± 1 SD, numbers reported with [ ] indicate a median            mandible branch and the occlusal
                         and IRQ. * versus ketoprofen 100 mg b.i.d. and # versus preoperative period.                           plane (16). In the present study,
Braz Dent J 29(2) 2018

although most of the lower third molars were classified          which NSAIDs present the highest risk of gastrointestinal
as IA (n = 24) according to Pell and Gregory and in the          complications. In a meta-analysis performed to assess the
vertical position (n = 27) according to Winter (16), there       risk of severe gastrointestinal complications associated
was a high level of surgical difficulty, since there was a       with 12 commonly used chronic NSAIDs, ibuprofen
need for osteotomy and tooth sectioning in the great             represented the lowest risk of gastrointestinal toxicity. In
majority of dental elements due to root dilaceration and         contrast, the relative risk (RR) of some NSAIDs compared
divergence, besides the degree of impaction, culminating         with ibuprofen (RR = 1) reached values of up to 3.8
with greater surgical trauma and, consequently, an increase      (piroxicam) and 4.2 (ketoprofen) (28). Ketoprofen 200 mg
in postoperative swelling and trismus.                           drug in combination with omeprazole 20 mg is new on the
     The clinical efficacy of ketoprofen in the control          market and is indicated for the symptomatic treatment
of postoperative pain after extractions of third molars          of rheumatoid arthritis and osteoarthritis in volunteers
has been widely described in clinical trials (5, 25). The        at risk of developing ulcer or erosions in the stomach,
use of ketoprofen 75 mg and acetaminophen 1,000 mg               duodenum or other part of the intestine with the use
was compared, showing lower levels of pain reported by           of NSAIDs. One study evaluated whether the effect of
volunteers who received ketoprofen, thus demonstrating           a dose of omeprazole would alter the pharmacokinetics
that even at lower doses ketoprofen is effective in the          of enteric ketoprofen and determined that omeprazole
control of postoperative pain (25).                              does not affect hepatic flow rate and is also a more
     Another parameter used to define the postoperative          direct agent for the inhibition of gastric acid production,
pain intensity of the volunteers in the present study was        offering advantages for the study of the effect of gastric
the amount of rescue analgesic medication (acetaminophen         acidity on the release of enteric coated products (29). The

                                                                                                                                   Ketoprofen with or without omeprazole for pain
750 mg) used which corroborate with many studies                 pharmacokinetic profiles of ketoprofen and omeprazole
evaluating the patient’s need to use pain relief medication,     components in this combination used in the present study
thus demonstrating the drug’s efficacy in pain modulation        are comparable to those of the separately administered
(4, 9). When volunteers took ketoprofen 100 mg b.i.d., they      ketoprofen and omeprazole components. There is no
consumed a greater amount of rescue analgesic medication         influence on the pharmacokinetics of ketoprofen when
compared to the use of ketoprofen of 200 mg + omeprazole         administered concomitantly with omeprazole (13-15,28).
20 mg q.d. (p=0.0026) to reduce postoperative pain. The               Following administration of both study drugs, no
mean time in hours for the volunteers to take the first tablet   adverse reactions were reported by the volunteers. This
of rescue analgesic medication, the results show that when       may be due to the fact that the NSAIDs administered were
they took ketoprofen 200 mg + omeprazole 20 mg q.d. was          for a short period of time, and volunteers did not have
5 h, whereas 7 h when they used ketoprofen 100 mg b.i.d.         any underlying disease, blood dyscrasias or drug allergy.
(p=0.53). The results differ of Pouchain et al. 2015 (26)             Based on the assumption that other methods for pain
compared the effect of nimesulide 100 mg and ketoprofen          assessment contribute to research adopting this type of
100 mg, both b.i.d., on the inflammatory parameters related      study model such as in the present study, global assessment
to the surgical removal of third molars, both administered       is a widely used tool offering a holistic view of drug efficacy
immediately after the surgical procedure, but the use of         in general patient conception (2, 8, 9, 18). Therefore,
pain relief drugs was considered unnecessary by volunteer.       ketoprofen 200 mg + omeprazole 20 mg b.i.d. shows lower
The data showed that although complete pain relief was           levels of postoperative pain in comparison to ketoprofen
not observed, the level of pain was tolerable to volunteers.     100 mg b.i.d., thus receiving an excellent classification in
     In contrast, the administration of several NSAIDs,          the global evaluation of the volunteers participating in
including ketoprofen, was evaluated in volunteers                this study. As described, the combination of ketoprofen
undergoing surgery for extraction of impacted third              200 mg + omeprazole 20 mg includes a prolonged release
molars and it was observed that 75% of the volunteers            form of ketoprofen and a gastroresistant release form of
consumed pain relief medication during the early onset of        omeprazole, both suitable for once-daily dosing (15). In
pain (3 h after the surgical procedure) and that 24% of the      addition, in comparison with other studies by our study
volunteers consumed pain relief medication immediately           group evaluating different NSAIDs in bilateral third molar
after the surgical procedure (27). In the present study, when    extraction model, ketoprofen 200 mg + omeprazole 20 mg
volunteers took ketoprofen 100 mg b.i.d., used significantly     b.i.d. showed as good pain control as other drugs evaluated
higher total amount of rescue analgesic medication               such as piroxicam, valdecoxib, etoricoxib, meloxicam,
compared to when took ketoprofen 200 mg + omeprazole             ketorolac, naproxen (1, 2, 8, 9, 21).
20 mg b.i.d. (76 vs. 50% respectively, p=0.001).                      In summary, the results of the present study revealed
     It is particularly important for the clinician to know      that when volunteers took ketoprofen 200 mg + omeprazole
Braz Dent J 29(2) 2018

                                                                                                               nonsteroidal anti-inflammatory drugs, ibuprofen and flurbiprofen,
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                                                                                                                                   Accepted March 18, 2018
      an observational, prospective, multicentre survey. Clin Drug Investig

                                                                                                                                                                    Ketoprofen with or without omeprazole for pain

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